Treating infections with ionizing radiation: a historical perspective and emerging techniques.

BACKGROUND: Widespread use and misuse of antibiotics have led to a dramatic increase in the emergence of antibiotic resistant bacteria, while the discovery and development of new antibiotics is declining. This has made certain implant-associated infections such as periprosthetic joint infections, where a biofilm is formed, very difficult to treat. Alternative treatment modalities are needed to treat these types of infections in the future. One candidate that has been used extensively in the past, is the use of ionizing radiation. This review aims to provide a historical overview and future perspective of radiation therapy in infectious diseases with a focus on orthopedic infections. METHODS: A systematic search strategy was designed to select studies that used radiation as treatment for bacterial or fungal infections. A total of 216 potentially relevant full-text publications were independently reviewed, of which 182 focused on external radiation and 34 on internal radiation. Due to the large number of studies, several topics were chosen. The main advantages, disadvantages, limitations, and implications of radiation treatment for infections were discussed. RESULTS: In the pre-antibiotic era, high mortality rates were seen in different infections such as pneumonia, gas gangrene and otitis media. In some cases, external radiation therapy decreased the mortality significantly but long-term follow-up of the patients was often not performed so long term radiation effects, as well as potential increased risk of malignancies could not be investigated. Internal radiation using alpha and beta emitting radionuclides show great promise in treating fungal and bacterial infections when combined with selective targeting through antibodies, thus minimizing possible collateral damage to healthy tissue. CONCLUSION: The novel prospects of radiation treatment strategies against planktonic and biofilm-related microbial infections seem feasible and are worth investigating further. However, potential risks involving radiation treatment must be considered in each individual patient.

Radioimmunotherapy of methicillin-resistant Staphylococcus aureus in planktonic state and biofilms.

BACKGROUND: Implant associated infections such as periprosthetic joint infections are difficult to treat as the bacteria form a biofilm on the prosthetic material. This biofilm complicates surgical and antibiotic treatment. With rising antibiotic resistance, alternative treatment options are needed to treat these infections in the future. The aim of this article is to provide proof-of-principle data required for further development of radioimmunotherapy for non-invasive treatment of implant associated infections. METHODS: Planktonic cells and biofilms of Methicillin-resistant staphylococcus aureus are grown and treated with radioimmunotherapy. The monoclonal antibodies used, target wall teichoic acids that are cell and biofilm specific. Three different radionuclides in different doses were used. Viability and metabolic activity of the bacterial cells and biofilms were measured by CFU dilution and XTT reduction. RESULTS: Alpha-RIT with Bismuth-213 showed significant and dose dependent killing in both planktonic MRSA and biofilm. When planktonic bacteria were treated with 370 kBq of 213Bi-RIT 99% of the bacteria were killed. Complete killing of the bacteria in the biofilm was seen at 185 kBq. Beta-RIT with Lutetium-177 and Actinium-225 showed little to no significant killing. CONCLUSION: Our results demonstrate the ability of specific antibodies loaded with an alpha-emitter Bismuth-213 to selectively kill staphylococcus aureus cells in vitro in both planktonic and biofilm state. RIT could therefore be a potentially alternative treatment modality against planktonic and biofilm-related microbial infections.

Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model.

Immunotherapy has changed the oncology landscape during the last decade and become standard of care for several cancers. The combinations of immunotherapy with other treatment modalities are also being investigated. One of the challenges to investigate such combinations is to identify suitable mouse models for the pre-clinical experiments. In the past, we and other researchers showed that murine B16-F10 melanoma in C57Bl6 mice is refractory to treatment with immune checkpoint inhibitors. In this work we studied the suitability of an alternative syngeneic model, Cloudman S91 murine melanoma in DBA/2 mouse (DBA/2NCrl), to study the combination of immunotherapy targeting PD-1 and radioimmunotherapy targeting melanin. DBA/2 male and female mice were injected subcutaneously with 3-6 million Cloudman S91 cells. When the tumors reached ~150 mm3 volume, the animals were treated intraperitoneally with PBS (sham), h8C3 unlabeled (cold) antibody to melanin, immunotherapy with anti-PD-1 antibody, radioimmunotherapy with 213Bismuth (213Bi)-labeled h8C3 antibody, or several combinations of immunotherapy and radioimmunotherapy. Treatments with immunotherapy alone produced very modest effect on the tumor size, while combination therapy resulted in significant slowing down of the tumor growth, increased animal survival, and no decrease in animal body weight. We conclude that Cloudman S91 murine melanoma in DBA/2 mouse is a suitable model to evaluate combination of immunotherapy of melanoma with tangentially targeted treatments.

Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy.

Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- and 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma.

Targeted radionuclide therapies for pancreatic cancer.

Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas.

Preclinical testing of radiopharmaceuticals for novel applications in HIV, bacterial and fungal infectious diseases.

Antibiotics, antifungal and antiviral medications have traditionally been used in the management of infections. Due to widespread emergence of resistance to antimicrobial medications, and their side effects, there is a growing need for alternative approaches for management of such conditions. Antibiotic resistant bacterial pathogens are on the rise. A cure has not been achieved for viral infections like AIDS, while fungal and parasitic infections are constant threats to the health of general public. The incidence of opportunistic infections in immunocompromised individuals like HIV patients, patients receiving high dose steroids, chemotherapy patients, and organ transplant recipients is on the rise. Radioimmunotherapy (RIT) has the potential to be a suitable and viable therapeutic modality in the arena of infection management. Provided the target-associated antigen is expressed by the target cells and minimally or not expressed by other tissues, selective targeting of radiation to target sites can be theoretically accomplished with relative sparing normal tissues from radiation exposure. In our laboratory we successfully demonstrated the effectiveness of RIT for treating infectious diseases. We targeted murine cryptococcosis with a mAb to the Cryptococcus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 ((213)Bi) or Rhenium-188 ((188)Re). We subsequently extended the applicability of RIT for treating bacterial and viral infections. One of the advantages of using RIT to treat infections as opposed to cancer is that, in contrast to tumor cells, cells expressing microbial antigens are antigenically very different from host tissues and thus provide the potential for exquisite specificity and low cross-reactivity. Ever increasing incidence of infectious pathologies, exhaustion of antimicrobial possibilities and rising drug resistance calls for use of alternative and novel therapeutic options and we believe RIT is the need of the hour to combat these infections.

Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer.

BACKGROUND: In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS: We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS: The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION: We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy.

166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: comparison with 188Re radiolabel.

INTRODUCTION: An approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a ß emitter (188)Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived ß emitters (90)Y and (166)Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy ß (E(max)>1.5 MeV) emission properties. METHODS: 6D2 was radiolabeled with longer lived ß emitters (90)Y and (166)Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed. RESULTS: When labeled with the longer lived (90)Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by (166)Ho-6D2 was very similar to the previously reported therapy results for (188)Re-6D2. In addition, (166)Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. CONCLUSIONS: (166)Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the (90)Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of (166)Ho to deliver the tumoricidal absorbed dose to the tumor. Further investigation of this radionuclide for RIT of melanoma is warranted.

Combined treatment of the experimental human papilloma virus-16-positive cervical and head and neck cancers with cisplatin and radioimmunotherapy targeting viral E6 oncoprotein.

BACKGROUND: Human papilloma virus (HPV) is implicated in >99% of cervical cancers and ∼40% of head and neck squamous cell carcinoma (HNSCC). We previously targeted E6 oncogene with (188)Rhenium-labelled monoclonal antibody (mAb) C1P5 to HPV16 E6 in cervical cancer and HNSCC. Intranuclear E6 can be accessed by mAbs in non-viable cells with leaky membranes. As radioimmunotherapy (RIT) efficacy depends on the availability of target protein-we hypothesised that pretreatment with cisplatin will kill some tumour cells and increase E6 availability for RIT. METHODS: Mice with subcutaneous HPV16+ cervical (CasKi) and HNSCC (2A3) tumours were pretreated with 0-7.5 mg kg(-1) per day cisplatin for 3 days followed by (188)Re-C1P5 and biodistribution was performed 24 h later. For RIT, the animals were treated with: 5 mg kg(-1) per day cisplatin for 3 days; or 5 mg kg(-1) per day cisplatin for 3 days followed 200 or 400µCi (188)Re-C1P5 mAb; or 200 or 400µCi (188)Re-C1P5 mAb; or left untreated, and observed for tumour growth for 24 days. RESULTS: Pretreatment with cisplatin increased the uptake of (188)Re-C1P5 in the tumours 2.5 to 3.5-fold and caused significant retardation in tumour growth for CasKi and 2A3 tumours in both RIT alone and cisplatin, and RIT groups in comparison with the untreated control and cisplatin alone groups (P<0.05). The combined treatment was more effective than either modality alone (P<0.05). CONCLUSION: Our study demonstrates that preceding RIT targeting E6 oncogene with chemotherapy is effective in suppressing tumour growth in mouse models of HPV16+ cancers.

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

There is a need for effective "broad spectrum" therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of (188)Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi (188)Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of (188)Re-6D2 was escalated to 54 mCi. SPECT/CT revealed (188)Re-6D2 uptake in melanoma metastases. The mean effective half-life of (188)Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that (188)Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

Toward developing a universal treatment for fungal disease using radioimmunotherapy targeting common fungal antigens.

BACKGROUND: Previously, we demonstrated the ability of radiolabeled antibodies recognizing the cryptococcal polysaccharide capsule to kill Cryptococcus neoformans both in vitro and in infected mice. This approach, known as radioimmunotherapy (RIT), uses the exquisite ability of antibodies to bind antigens to deliver microbicidal radiation. To create RIT reagents which would be efficacious against all major medically important fungi, we have selected monoclonal antibodies (mAbs) to common surface fungal antigens such as heat shock protein 60 (HSP60), which is found on the surface of diverse fungi; beta (1,3)-glucan, which is a major constituent of fungal cell walls; ceramide which is found at the cell surface, and melanin, a polymer present in the fungal cell wall. METHODS: MAbs 4E12, an IgG2a to fungal HSP60; 2G8, an IgG2b to beta-(1,3)-glucan; and 6D2, an IgM to melanin, were labeled with the alpha particle emitting radionuclide 213-Bismuth ((213)Bi) using the chelator CHXA". B11, an IgM antibody to glucosylceramide, was labeled with the beta emitter 188-Rhenium ((188)Re). Model organisms Cryptococcus neoformans and Candida albicans were used to assess the cytotoxicity of these compounds after exposure to either radiolabeled mAbs or controls. RESULTS: (213)Bi-mAbs to HSP60 and to the beta-(1,3)-glucan each reduced the viability of both fungi by 80-100%. The (213)Bi-6D2 mAb to melanin killed 22% of C. neoformans, but did not kill C. albicans. B11 mAb against fungal ceramide was effective against wild-type C. neoformans, but was unable to kill a mutant lacking the ceramide target. Unlabeled mAbs and radiolabeled irrelevant control mAbs caused no killing. CONCLUSION: Our results suggest that it is feasible to develop RIT against fungal pathogens by targeting common antigens and such an approach could be developed against fungal diseases for which existing therapy is unsatisfactory.

Treatment of infection with radiolabeled antibodies.

The field of infectious diseases is in urgent need of new approaches to antimicrobial therapy. Radio-immunotherapy (RIT) has evolved into successful therapy for certain malignancies. Published preclinical and clinical investigations have demonstrated that radiolabeled microorganism-specific antibodies localize to tissue sites of bacterial and fungal infection. The potential of RIT as an antimicrobial treatment strategy has not been developed clinically, which could reflect lack of awareness of the difficult problems in clinical infectious diseases by the nuclear medicine community and of RIT by the infectious diseases physicians. We have recently demonstrated the feasibility of using RIT for treating murine cryptococcosis using a monoclonal antibody to Crypto-coccus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 or Rhenium-188. Subsequently, we showed the applicability of RIT to bacterial (Streptococcus pneumonia) and viral (HIV-1) infections. Treatment did not cause acute hematologic toxicity in treated animals. The mechanisms of RIT of infection include killing of microbial cells by ''direct hit'' and ''cross-fire'' effects, promotion of apoptosis-like death, cooperation with macrophages and modulation of the inflammatory response. RIT for infection is theoretically useful for any microbe susceptible to radiation, including bacteria, fungi, viruses and parasites. The promise of this technique is based on the fact that the technology is largely in place and that the only requirements are availability of microbe-specific monoclonal antibodies and suitable radionuclides. In fact, one could anticipate that targeting microbes will be easier than targeting neoplastic cells when the enormous antigenic differences between host and microbes are taken into consideration. However, considerable basic work remains to be done to ascertain the optimal conditions for the efficacy of RIT for infection.

Antibody-guided alpha radiation effectively damages fungal biofilms.

The use of indwelling medical devices--pacemakers, prosthetic joints, catheters--is rapidly growing and is often complicated by infections with biofilm-forming microbes that are resistant to antimicrobial agents and host defense mechanisms. We investigated for the first time the use of microbe-specific monoclonal antibodies (MAbs) as delivery vehicles for targeting biofilms with cytocidal radiation. MAb 18B7 (immunoglobulin G1 [IgG1]), which binds to capsular polysaccharides of the human pathogenic fungus Cryptococcus neoformans, penetrated cryptococcal biofilms, as shown by confocal microscopy. When the alpha radiation-emitter 213-Bismuth ((213)Bi) was attached to MAb 18B7 and the radiolabeled MAb was added to C. neoformans biofilms, there was a 50% reduction in biofilm metabolic activity. In contrast, when the IgM MAb 13F1 labeled with (213)Bi was used there was no penetration of the fungal biofilm and no damage. Unlabeled 18B7, (213)Bi-labeled nonspecific MAbs, and gamma and beta types of radiation did not have an effect on biofilms. The lack of efficacy of gamma and beta radiation probably reflects the radioprotective properties of polysaccharide biofilm matrix. Our results indicate that C. neoformans biofilms are susceptible to treatment with antibody-targeted alpha radiation, suggesting a novel option for the prevention or treatment of microbial biofilms on indwelling medical devices.

Radiological studies reveal radial differences in the architecture of the polysaccharide capsule of Cryptococcus neoformans.

The polysaccharide capsule of the pathogenic fungus Cryptococcus neoformans is an important virulence factor, but relatively little is known about its architecture. We applied a combination of radiological, chemical, and serological methods to investigate the structure of this polysaccharide capsule. Exposure of C. neoformans cells to gamma radiation, dimethyl sulfoxide, or radiolabeled monoclonal antibody removed a significant part of the capsule. Short intervals of gamma irradiation removed the outer portion of the cryptococcal capsule without killing cells, which could subsequently repair their capsules. Survival analysis of irradiated wild-type, acapsular mutant, and complemented mutant strains demonstrated that the capsule contributed to radioprotection and had a linear attenuation coefficient higher than that of lead. The capsule portions remaining after dimethyl sulfoxide or gamma radiation treatment were comparable in size, 65 to 66 microm3, and retained immunoreactivity for a monoclonal antibody to glucuronoxylomannan. Simultaneous or sequential treatment of the cells with dimethyl sulfoxide and radiation removed the remaining capsule so that it was not visible by light microscopy. The capsule could be protected against radiation by either of the free radical scavengers ascorbic acid and sorbitol. Sugar composition analysis of polysaccharide removed from the outer and inner parts of the capsule revealed significant differences in glucuronic acid and xylose molar ratios, implying differences in the chemical structure of the constituent polysaccharides. Our results provide compelling evidence for the existence of two zones in the C. neoformans capsule that differ in susceptibility to dimethyl sulfoxide and radiation and, possibly, in packing and composition.

Feasibility of radioimmunotherapy of experimental pneumococcal infection.

Streptococcus pneumoniae is an important cause of community-acquired pneumonia, meningitis, and bacteremia. The problem of pneumococcal disease is exacerbated by increasing drug resistance. Furthermore, patients with impaired immunity are at high risk for invasive pneumococcal infections. Thus, there is an urgent need for new approaches to antimicrobial therapy. Antibody therapies take advantage of the specificity and high affinity of the antigen-antibody interaction to deliver antibacterial compounds to a site of infection in the form of naked or conjugated antibodies. We have recently established that radioimmunotherapy (RIT) can be used to treat experimental fungal infections in mice. In the present study, we investigated the feasibility of applying a RIT approach to the treatment of S. pneumoniae infection by evaluating the susceptibility of S. pneumoniae to radiolabeled antibody in vitro and in an animal infection model. For the specific antibody carrier, we used human monoclonal antibody D11, which binds to pneumococcal capsular polysaccharide 8. We have selected the alpha particle emitter (213)Bi as the radionuclide for conjugation to the antibody. Incubation of serotype 8 S. pneumoniae with (213)Bi-D11 resulted in dose-dependent killing of bacteria. RIT of S. pneumoniae infection in C57BL/6 mice showed that 60% more mice survived in the (213)Bi-D11-treated group (80 micro Ci) than in the untreated group (P < 0.01). The treatment did not cause hematological toxicity, as demonstrated by platelet counts. This feasibility study establishes that RIT can be applied to the treatment of bacterial infections.

Evaluation of acute hematologic and long-term pulmonary toxicities of radioimmunotherapy of Cryptococcus neoformans infection in murine models.

We evaluated acute hematological and long-term pulmonary toxicity of radioimmunotherapy in murine models of Cryptococcus neoformans infection. Activities up to 250 microCi were well tolerated by healthy A/JCr mice for (213)Bi-18B7 and (188)Re-18B7 monoclonal antibodies. In infected mice, doses up to 150 microCi produced only transient toxicity. The lungs of treated mice had no evidence of radiation fibrosis.

Development of a titanium tungstate-based 188W/188Re gel generator using tungsten of natural isotopic abundance.

The feasibility of developing titanium tungstate-based 188W/188Re gel generator using tungsten of natural isotopic abundance irradiated in a moderate flux reactor has been investigated. Influence of temperature, pH and eluent concentration on generator performance was studied. It was found that "post-formed" approach allows to construct gel generators with elution performance and 188Re elution yields very close to those of conventional alumina 188W/188Re generator. Curie-level 185W radionuclidic impurity presents a challenge during the processing of target material and subsequent elution of the generator. In the future use of semi-enriched with 186W target material (50-60% enrichment) would be beneficial in the development of titanium tungstate-based 188W/188Re gel generators.

Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS).

The sodium-iodide symporter (NIS), which transports iodine into the cell, is expressed in thyroid tissue and was recently found to be expressed in approximately 80% of human breast cancers but not in healthy breast tissue. These findings raised the possibility that therapeutics targeting uptake by NIS may be used for breast cancer treatment. To increase the efficacy of such therapy it would be ideal to identify a radioactive therapy with enhanced local emission. The feasibility of using the powerful beta-emitting radiometal (188)Re in the form of (188)Re-perrhenate was therefore compared with 131I for treatment of NIS-expressing mammary tumors. In the current studies, using a xenografted breast cancer model induced by the ErbB2 oncogene in nude mice, (188)Re-perrhenate exhibited NIS-dependent uptake into the mammary tumor. Dosimetry calculations in the mammary tumor demonstrate that (188)Re-perrhenate is able to deliver a dose 4.5 times higher than (131)I suggesting it may provide enhanced therapeutic efficacy.

Recent advances in radionuclide therapy.

A variety of radionuclides continue to be investigated and/or clinically used for different therapeutic applications in nuclear medicine. The choice of a particular radionuclide with regard to appropriate emissions, linear energy transfer, and physical half-life is dictated to a large extent by the character of the disease (eg, solid tumor or metastatic disease) and by the carrier used to selectively transport the radionuclide to the desired site. An impressive body of information has appeared in the recent literature that addresses many of these considerations. This article summarizes and discusses the many recent advances and the progress in the clinical applications of therapeutic radionuclides in relatively new and developing areas, such as radioimmunotherapy, peptide therapy, intravascular therapy to prevent restenosis, radiation synovectomy, and bone malignancy therapy. Projections are made as to the future directions and progress in these areas. The crucial issue of a reliable, year-round supply of new and emerging therapeutic radionuclides in quantities sufficient initially for research, and then for routine clinical use, is a very worthy goal which, in the United States, remains to be achieved.

Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody.

UNLABELLED: Monoclonal antibodies (mAbs) labeled with alpha-emitting radionuclides such as (211)At, (212)Bi, (213)Bi, and (212)Pb (which decays by beta-emission to its alpha-emitting daughter, (212)Bi) are being evaluated for their potential applications for cancer therapy. The fate of these radionuclides after cells are targeted with mAbs is important in terms of dosimetry and tumor detection. METHODS: In this study, we attached various radionuclides that result in alpha-emissions to T101, a rapidly internalizing anti-CD5 mAb. We then evaluated the catabolism and cellular retention and compared them with those of (125)I- and (111)In-labeled T101. T101 was labeled with (211)At, (125)I, (205,6)Bi, (111)In, and (203)Pb. CD5 antigen-positive cells, peripheral blood mononuclear cells (PBMNC), and MOLT-4 leukemia cells were used. The labeled T101 was incubated with the cells for 1 h at 4 degrees C for surface labeling. Unbound activity was removed and 1 mL medium added. The cells were then incubated at 37 degrees C for 0, 1, 2, 4, 8, and 24 h. The activity on the cell surface that internalized and the activity on the cell surface remaining in the supernatant were determined. The protein in the supernatant was further precipitated by methanol for determining protein-bound and non-protein-bound radioactivity. Sites of internal cellular localization of radioactivity were determined by Percoll gradient centrifugation. RESULTS: All radiolabeled antibodies bound to the cells were internalized rapidly. After internalization, (205,6)Bi, (203)Pb, and (111)In radiolabels were retained in the cell, with little decrease of cell-associated radioactivity. However, (211)At and (125)I were released from cells rapidly ((211)At < (125)I) and most of the radioactivity in the supernatant was in a non-protein-bound form. Intracellular distribution of radioactivity revealed a transit of the radiolabel from the cell surface to the lysosome. The catabolism patterns of MOLT-4 cells and PBMNC were similar. CONCLUSION: (211)At catabolism and release from cells were somewhat similar to that of (125)I, whereas (205,6)Bi and (203)Pb showed prolonged cell retention similar to that of (111)In. These catabolism differences may be important in the selection of alpha-radionuclides for radioimmunotherapy.